6-acylamino-penicillanic acid azides



United States Patent Oflice 3,454,556 Patented July 8, 1969 ABSTRACT OFTHE DISCLOSURE 6-substituted-penicillanic acid azides are usefulintermediates in the preparation of 6-substituted-penicillanylcarbamates, a new class of compounds that are smooth muscle-relaxants.In one of several processes, benzylpenicillin triethylammonium salt intetrahydrofuran was treated with ethylchloroformate to produce thebenzylpenicillanie acid mixed anhydride. A solution of sodium azide wasadded to the in situ mixed anhydride to produce benzylpenicillanic acidazide. The acid azide is subsequently reduced to the penicillanylalcohol which is further condensed with an isocyanate to produce apenicillanyl carbamate.

Cross-references to related applications This application is a divisionof our co-pending application Ser. No. 325,138, filed Nov. 20, 1963 andissued Mar. 28, 1967 as United States Patent 3,311,609.

Background of the invention Field of the invention.This inventionrelates to chemical compounds useful, for example, as intermediates inthe preparation of smooth muscle-relaxants and, more particularly to6-substituted-penicillanic acid azides which are valuable intermediatesin the ultimate preparation of 6-substitutedpenicillanyl carbamates, anew class of smooth muscle-relaxants.

Description of the prior art.--The 6-substituted-penicillanic acidazides of the instant invention and their usefulness as intermediates inthe preparation of the corresponding penicillanyl alcohols by aborohydride reduction were heretofore unknown in the art.

Summary of the invention The 6-substituted-penicillanic acid azides ofthe present invention are compounds having the formula wherein R isamino, acylamino, benzyloxycarbonylamino, phthalimido or tritylamino.

The preferred series of compounds is that of the formula in which Rrepresents the side chain of any of the penicillins.

Disclosure This invention relates to novel acid azide intermediateswhich are useful in the preparation of smooth muscle relaxants and, moreparticularly, to 6-suhstituted-penicillanic acid azide intermediateswhich are useful in the preparation of 6-substituted-penicillanylcarbamates.

There is thus provided, according to the present inven tion the seriesof compounds having the formula 0 l O=CN-CH Ng wherein R is amino,acylamino, benzyloxycarbonylamino, phthalimido or tritylamino.

The preferred series of compounds is that of the formula in which Rrepresents the side chain of any of the known penicillins other thanthose containing a group which is altered by reaction with sodiumborohydride such as a ketonic carbonyl. It is this series which may benamed 6-(substituted formamido)penicillanic acid azides.

Other known penicillins include those disclosed in U.S. Patents2,941,995; 2,951,839; 2,996,501; 3,007,920; 3,025,290; 3,035,047;3,040,032; 3,040,033; 3,041,332; 3,041,333; 3,043,831; 3,053,831;3,071,575; 3,071,576; 3,082,204; 3,093,547 and 3,093,633 and in Britishpatent specifications 874,414; 874,416; 876,516; 876,662; 877,120;877,531 878,233; 880,042; 880,400; 882,335; 888,110; 888,552; 889,066;889,069; 889,070; 889,168; 889,231; 890,201; 891,279; 891,586; 891,938;893,518; 894,247; 894,460; 896,072; 899,199; 900,666; 905,778; 906,383;908,787; 914,419; 916,097; 916,204; 916,488; 920,176; 920,177; 920,300;921,513; 922,278; 924,037 and 925,281 and in Belgian Patents 593,222;595,171; 597,859; 602,- 494; 603,703; 609,039; 616,419 and 617,187 andin South African patent applications 60/2882; 60/3057; 60/3748; 61/1649;R61/2751; 62/54; 62/4920; 63/1612 and 63/2423.

Preferred compounds of the present invention are those of the formulae 0S CH3 1 NH CH Cs MH, I O O The term (lower)alkyl as used herein meansboth cals having from one to ten carbon atoms such as methyl,

another group, e.g., (lower) alkoxy, it refers to the alkyl Preferredembodiments of the present invention are the restricted series ofcompounds of the following forif CNHCH hydropyridino,N-(lower)alkylpiperazino, N-phenyl-piperzino,N-(lower)alkyl(lower)alkylpiperazino, N-(loWer)alkyl-di-(lower)alkylpiperazino, furfurylamino, tetrahydrofurfurylamino,N-(lower)alkyl-N-furfurylamino, N-

5 alkyl-N-anilino or (lower)a1koxy-anilino; Z Z and Z each represent amember selected from the group consisting of (lower)alkyl and themonovalent radical of the formula.

wherein R R and R are each hydrogen, chloro,

bromo, iodo, trifluoromethyl, nitro, (lower)alkyl or (lower)alkoxy; Rrepresents (lower)alkyl, (lower)cycloalkyl, naphthyl, benzyl orphenethyl; and Ar represents the monovalent radical of the formulawherein R R and R are each a member selected from the group consistingof hydrogen, chloro, bromo, iodo, trifluoromethyl, phenyl, (lower)alkyland (lower)alkoxy,

but only one R group may represent phenyl.

straight and branched chain aliphatic hydrocarbon radiethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, amyl,

or hexyl, Z-ethylhexyl, heptyl, decyl, etc. Similarly, where the term(lower) is used as part of the description of portion of such groupwhich is therefore as described above in connection with (lower)alkyl.

mula.

wherein R represents (lower)alkyl;

wherein R represents (lower) alkyl and R is hydrogen or chloro;

CH3 CCH3 C-CHa i t /CH CCH3 0 ll C-CH:

wherein R represents hydrogen, amino, carbobenzoxyamino, phenyl, fiuoro,chloro, bromo, iodo, hydroxy, or (lower)alkanoyloxy including especiallyacetoxy or (lower)alkoxy; X represents oxygen or sulfur; R and R eachrepresent hydrogen, phenyl, or (lower)alkyl; R represents (lower)alkyl;R and R each represent (lower) alkyl, or Ar and at least one of R and Rrepresents (lower)alkyl; R represents (lower)alkylamino, di(lower)alkylamino, cycloalkylamino having from 3 to 7 carbon atoms inclusive,allylamino, diallylamino, phenyl(lower) 7O alkylamino, morpholino,lower(alky)morpholino, di- (lower)alky1morpholino, morpholino (lower)alkylamino, pyrrolidino, (lower)alkylpyrrolidino,di(lower)alkylpyrrolidino, N,N-hexamethyleneimino, piperidino, lower(alkyl)piperidino, di(lower)akiylpiperidino, 1,2,5,6tetrawherein R is(lower)alkyl; and

i CH

CCHs

wherein R is (lower)alkyl; and the individual compounds of the followingformulae A preferred starting material used in the process of thepresent invention is a mixed anhydride of a penicillin with anothercarboxylic acid, including a monoester, and particularly a loweraliphatic ester, of carbonic acid. Treatment of the mixed anhydride withan inorganic azide, e.g., sodium azide, yields the penicillin acid'azide which is then converted to the desired penicillanyl'alcohol byreaction With an alkali metal borohydride, e.g., sodium borohydride.Alternatively, the penicillin mixed anhydride is reacted directly withsuch a borohydride to produce the same penicillanyl alcohol.

One method which may be used to obtain the compounds of the presentinvention involves as its first step, the reaction of an inorganic azidesuch as sodium azide with a mixed anhydride of the penicillin. Theproduction of mixed anhydrides of carboxylic acids is known. Briefly,the acid is treated with enough base, such as triethylamine, to form thesalt and then with a reagent such as an alkyl chlorocanbonate or anorgano sulfonyl chloride to form the mixed anhydride. The followingequations exemplify this reaction:

2 5)a RCHzC 02H -i o 0 CIC 02C2H5 (U) H RCHaCOzH-N(C2H5)s RCH; 0000211In preparing a mixed anhydride of a penicillin, a salt of thepenicillin, such as the potassium, sodium or triethylamine salt, isreacted with a reagent such as an alkyl halocarbonate, (e.g., ethylchloroformate) or an organo (preferably alkyl or aryl)sulfonyl chloride,(e.g. p-toluenesulfonyl chloride or methanesulfonyl chloride). Thereaction may be represented as follows:

wherein R is as previously described; M is a cation such as potassium,sodium or the triethylamino radical; and

Y represents an alkyl carbonate or an organo (preferably alkyl oraryl)-sulfonyl gronpi.e., Y may be, for example, COOCH CH or SO CH Thereaction is preferably conducted in the presence of a non-reactivesolvent such as methylene chloride. The reaction conditions may varywidely and are not critical. Thus, the temperature may range from about-30 C. up to the reflux temperature of the solution. The proportions mayalso be varied widely. It is preferred to use from one to two moles ofthe anhydride forming reagent per mole of penicillin salt.

After the mixed anhydride of the penicillin has been prepared, it isreacted with an inorganic azide such as sodium azide. The reaction maybe conducted in the presence of a solvent such as tetrahydrofuran andthe azide is preferably added in aqueous solution. The temperature atwhich the reaction is conducted may vary between about 40 C. and roomtemperature. The proportions of reactants may also be varied widely. Itis preferred that from about one-half to two moles (and usually aboutone mole) of azide per mole of the penicillin mixed anhydride be used.After the reaction with a borohydride is complete, pure penicillanylalcohol may be recovered by removal of the solvent and recrystallizationof the product.

One equivalent of the alcohols resulting from the borohydride treatmentof the penicillanic acid azide is further treated with from one to threeequivalents of phenylisocyanate to produce the ultimate product desired,a muscle-relaxing 6-(substituted formamido)penicillanylcarbamate havingthe general formula wherein R is amino, acylamino, benzyloxycarbonyLamino, phthalimido or tritylamino and R is arylcarbarnoyl (-CONHAr) andespecially phenylcarbamoyl. Use of a non-hydroxylic solvent such asmethylene chloride, benzene or dimethylformamide is preferred; thereaction proceeds more quickly at elevated temperatures, e.g. at thereflux temperature of the solvent, but can be conducted at roomtemperature.

Each of the penicillin alcohols described above is I prepared from thecorresponding acid azide as set forth above in general and asexemplified in detail in the examples below. Thus these acid azides havethe grouping in place of the CH OH group of the corresponding penicillinalcohol. For purposes of additional chemical identification, analysisand the like it is desirable to convert these acid azides to thecorresponding isocyanates having the substituent NCO in place of thegroup; this transformation is easily performed by heating the azidemildly or by placing it in a vacuum, e.g. for several days at roomtemperature. These isocyanates, which may be named 6-substitutedamido-2,2-dimethyl- 3-penamyl isocyanates, are also reactiveintermediates for further chemical transformations.

The following examples will serve to illustrate the invention, which isnot limited thereto. All temperatures are given in degrees centigrade.

8 Description of the preferred embodiments Example 1 g /S\ /CH3Q-CHr-C-NH CHCH C-CH:

lC |-1 T-HCHa-OH o 6-phenylacetamidopenicillanyl alcohol-A suspension of43.5 g. (0.10 mole) of benzylpenicillin triethylammonium salt in 300 ml.of tetrahydrofuran was cooled to 10 and a solution of 10.8 g. (0.10mole) of ethyl chloroformate in 50 ml. of tetrahydrofuran was added. Theresulting mixture was stirred at -10 for two hours, when the solutionbecame clear. Then a solution of 6.5 g. 0.10 mole) of sodium azide in 50ml. of water was added dropwise during a period of thirty minutes toform benzylpenicillin acid azide. The reaction mixture was diluted with100 ml. of ice water, and 7.4 g. (0.20 mole) of sodium borohydride wasadded in small portions during the next thirty minutes to form theproduct, 6-phenylacetamidopenicillanyl alcohol. This stage of thereaction was carried out at 0-5", and the pH was maintained in the rangeof 6 to 8 by occasional additions of glacial acetic acid. The solutionwas acidified to pH 6.0 with glacial acetic acid, diluted with 500 ml.of water and extracted with three 250 ml. portions of methylenechloride. The combined methylene chloride extracts containing theproduct were dried over anhydrous sodium sulfate, filtered and thesolvent was removed by vacuum distillation at 33 to leave as the residuethe product, which was prepared for analysis by solution in 300 ml. ofdry ethyl acetate, filtration and complete removal of the solvent undervacuum to give 25 g. (78% yield). The infrared absorption spectrumincluded maxima for OH at 3280; B-lactam at 1770; amide at 1660 and1530; primary alcohol at 1042; aromatic at 730 and 700 cm.-

Analysis.--Calcd for C H N O S: C, 59.99; H, 6.29; N, 8.75. Found: C,59.65; H, 6.03; N, 8.63.

6-phenylacetamidopenicillanyl alcohol phenylcarbamate.-A solutioncontaining 8.0 g. (0.025 mole) of 6- phenylacetamidopenicillanyl alcoholand 6.0 g. (0.050 mole) of phenylisocyanate in 50 ml. of methylenechloride was stirred at room temperature for one-half hour and thenheated to reflux for five minutes. It was cooled, filtered, and dilutedto the cloud point with petroleum ether (Skellysolve B, boiling point4060). On standing for fifteen hours, 11 g. (100%) of the crude, crystalline product, 6-phenylacetamidopenicillanyl alcohol phenylcarbamate, wascollected by filtration. It was recrystallized from 250 ml. of isopropylalcohol to give 10.0 g. of purified product, M.P. 129 130. The infraredspectrum of this material had characteristic absorption maxima for NH at3270; Blactam at 1785; carbamate at 1710; amide at 1660; and aromatic at770 and 695 cmf Analysis.-Calcd for C H N O S: C, 62.85; H, 5.73; N,9.58. Found: C, 62.50; H, 5.57; N, 9.68.

6-phenylacetamidopenicillanyl acetate.A solution of 1.531 g. (4.77millimoles) of 6-phenylacetamidopenicillanyl alcohol in 20 ml. of aceticanhydride was heated on a steam bath for thirty minutes. The excessacetic anhydride was removed by vacuum codistillation with benzene at50. The residue was vacuum-dried over phosphorus pentoxide to yield theproduct, 6-phenylacetamidopenicillanyl acetate, as 1.734 g. of stiffgum. Th product was dissolved in 150 ml. of ether and extracted with two100 ml. portions of 9% sodium bicarbonate solution, washed with water,dried over sodium sulfate and filtered. The purified product wasprecipitated from the filtrate by dilution with pentane. The resultinggum, 640 mg, was dried to a fluff under vacuum. Its infrared absorptionspectrum in chloroform showed maxima for NH at 3410; fi-lactam at 1780;ester at 1740; amide at 1675; ester at 1215; and aromatic at 785 and 670cmr Analysis.Calcd for C H N O S: C, 59.93; H, 6.15; N, 7.77. Found: C,59.40; H, 6.08; N, 7.90.

CCH3 O Potassium 6-phenylacetamidopenicillanyl alcohol acidsuccinate.--A mixture of 16.0 g. (0.050 mole) of6-phenylacetamidopenicillanyl alcohol, 6.0 ml. of triethylamine, 5.0 g.(0.050 mole) of succinic anhydride, and 200' ml. of methylene chloridewas stirred for one hour at room temperature and one hour at reflux. Thesolvent was removed under reduced pressure and the residue was dissolvedin 500 ml. of 2.5% aqueous sodium bicarbonate It was extracted with 300ml. of ether (discarded) and the aqueous solution was cooled in an icebath. To this cooled solution was added 400 ml. of methyl isobutylketone and sufficient 40% phosphoric acid to lower the pH to 2. Themethyl isobutyl ketone extract was washed with water, dried briefly oversodium sulfate, filtered, and to it was added 25 ml. of 50% potassium2-ethylhexanoate in n-butanol. The product, potassium6-phenylacetamidopenicillanyl alcohol acid succinate, settled to thebottom as an oil which was dissolved in 400 ml. of dry acetone, fromwhich it crystallized, 10.0 g., M.P. 149150 (dec.). The infraredabsorption spectrum of this compound matched the expected structure,with maxima for NH at 3300; ,EI-lactam at 1780; ester at 1725; amide at1680; carboxylate at 1580; and aromatic at 700 GEL-1.

Analytris.Calcd for C H N O SK: C, 52.40; H, 5.06; N, 6.12. Found: C,52.40; H, 5.07; N, 6.27.

O O S CH3 6-phenylacetamidopenicillanyl alcohol sulfone.A solutioncontaining 640 mg. (2.00 millimoles) of 6-phenyl acetamidopenicillanylalcohol in 15 ml. of acetone (which had been distilled from potassiumpermanganate) and 35 ml. of water was cooled to To this stirred solutionwas added dropwise a solution containing 632 mg. (4.00 millimoles) ofpotassium permanganate and 0.2 ml. of 85% phosphoric acid at such a ratethat the temperature did not exceed 10. The pH of the reaction mixturewas kept in the range 6.5-7.5 by occasional addition of 20% sodiumhydroxide solution. When the addition was completed, the mixture wasstirred for twenty minutes at 510 and the excess permanganate was thendestroyed by addition of aqueous sodium bisulfite. The precipitatedmanganese dioxide was removed by filtration, and the pH of the filtratewas adjusted to 2 with 40% phosphoric acid. The solution was extractedtwice with 50 ml. portions of methyl isobutyl ketone and the combinedextracts were washed with cold water and dried over magnesium sulfate.On evaporation of the solvent, the product,6-phenylacetamidopenicillianyl alcohol sulfone, remained as a gum whichwas redissolved in a few ml. of methyl isobutyl ketone and diluted withpetroleum ether (Skellysolve B). The product precipitated a white,crystalline solid, mg., M.P. 137139. Recrystallization from ethylacetate and Skellysolve B afforded an analytically pure sample, 45 mg.,M.P. 139-140. Its infrared absorption spectrum exhibited the expectedshift of the ,B-lactam to 1800, along with characteristic sulfone bandsat 1320 and 1120 emf- Other bands found were OH and NH at 3400; amide at1680 and 1520; and aromatic at 740 cmf Analysis.-Calcd for C H N O S: C,54.54; H, 5.72; N, 7.45. Found: C, 54.80; H, 5.71; N, 8.05.

6(d,1-u-phenoxypropionamido) penicillanyl alcohol. A solution of 20.2 g.(0.05 mole) of potassium 6-(d,lot-phenoxypropionamido)-penicillanate inml. of water was layered with ether, cooled, and acidified to pH 2 with42% phosphoric acid. The ether layer was separated, washed withsaturated NaCl solution, filtered through anhydrous Na SO and treatedwith 7.0 ml. (0.05 mole) of triethylamine. The precipitated gum wasdissolved by the addition of ml. of methylene chloride and the solutionwas concentrated to an oil in vacuo at 30. The oil was dissolved in 200ml. of tetrahydrofuran and concentrated by removal of 90 ml. of solventunder reduced pressure. After the addition of 50 ml. of tetrahydrofuran,the stirred solution was cooled to 10 and 5.4 g. (0.05 mole) of ethylchloroformate was added during 10 minutes. The mixture was stirred forone hour at l0 and treated during 15 minutes with a solution of 3.2 g.(0.05 mole) of sodium azide in 30 ml. of water. There was then added 3.8g. (0.10 mole) of sodium borohydride in small portions during 20minutes, the temperature being maintained at 0. The pH was kept at 88.5by occasional addition of glacial acetic acid. After dilution with 250ml. of water, the reaction mixture was extracted three times withmethylene chloride. The combined extracts were washed with water, driedover anhydrous Na SO and concentrated in vacuo to give 12.0 g. of theproduct, 6-(d,l-a-phenoxypropionamido)-penicillanyl alcohol, as a paleyellow oil.

Analysis.Calcd for C17H22N204S: C, H, N, 8.00. Found: C, 57.7; H, 6.29;N, 8.20.

Infrared (KBr) (cmf 1685 (amide), 1785 (fl-lactam).

6-( d,l-a-phenoxypropionamido) penicillanyl alcohol phenylcarbamate.-Asolution of 3.0 g. (8.5 millimole) of6-(d,l-oc-phenoxypropionamido)penicillanyl alcohol in 25 ml. of drybenzene was treated with 1.1 ml. (10 millimole) of phenylisocyanate.After 7 days at room temperature the solution was concentrated and theresidual amber gum was dissolved in ether, from which the product,6-(d,l-a-phenoxypropionamido)-penicillanyl alcohol phenylcarbamate,crystallized on scratching. The white product was recrystallized frombenzene and petroleum ether (Skellysolve B) to yield 1.05 g., M.P. 168.The infrared absorption spectrum was consistent with the expectedstructure, having maxima for NH at 3345; ,B-lactam at 1787; carbamate at1739; amide at 1680; phenyl ether at 1225; aromatic bands at 1600, 760and 695 cmf Analysis.Calcd for C H N O S: C, 61.38; H, 5.80; N, 8.95.Found: C, 61.00; H, 5.63; N, 8.90.

1 1 Example 3 OCH3 O S CH3 6-(2',6'-dimethoxybenzamido) penicillanylalcohol.- A solution of 50 g. (0.119 mole) of sodium6-(2,6-dimethoxybenazrnido)-penicillanate monohydrate in 500 m1. ofwater was acidified with 42% phosphoric acid and extracted with 500 ml.of methylene chloride in two portions. The combined methylene chlorideextracts were dried with sodium sulfate, filtered and the filtratetreated with 17 ml. (0.12 mole) of triethylamine. The solvent wasremoved at reduced pressure to give triethylammonium6-(2,6-dimethoxybenz-amido)-penicillanate as an oil.

To a solution of approximately 0.119 mole of triethylammonium6-(2,6-dimethoxybenzamido)-penicillanate in 300 ml. of tetrahydrofuranat 10 was added dropwise 11.4 ml. (0.119 mole) of ethyl chloroformateover a period of ten minutes. After stirring for one hour at l asolution of 7.7 g. (0.118 mole) of sodium azide in 50 ml. of water wasadded dropwise over a period of 30 minutes at -10 to 12. The reactionmixture was stirred for 15 minutes and 100 m1. of water was added, thetemperature being maintained at 0 to The mixture was adjusted to pH 8.0with 20% sodium hydroxide. Nine g. (0.238 mole) sodium borohydride wasadded in small portions over a period of one-half hour. The reactionmixture was maintained at pH 8.0 to 8.5 by the addition of either 20%sodium hydroxide or glacial acetic acid as needed. After stirring forone-half hour at 0 to 5 the reaction mixture was adjusted to pH 7 with 6N hydrochyloric acid, diluted with 500 ml. of water and extracted with500 ml. of methylene chloride. The methylene chloride extract was washedwith 500 ml. of water, dried with sodium sulfate and filtered. Thesolvent was distilled at reduced pressure to give the product, 6-(2',6'- dimethoxybenzamido)- penicillanyl alcohol, as a viscous oil; yield35 g.

-A portion of the oil after approximately one week had partiallycrystalized. Ethyl acetate was added and the mixture stored for 2 hoursat room temperature, then cooled in an ice bath and the crystallineproduct collected by filtration; M.P. 146148.

Analysis.-Calcd fOl' C1'7H22N205S: C, H, N, 7.65. Found: C, 55.20; H,5.93; N, 7.75.

OCH:

1 S OH;

6-(2,6 dimethoxybenzamido) penicillanyl alcohol phenylcarbamate.Asolution of 3.7 g. (0.010 mole) of 6 (2,6 dimethoxybenzamido)penicillanyl alcohol and 1.19 g. (0.010 mole) of phenylisocyanate in 25ml. of methylene chloride was stored at room temperature for 20 hours.An additional 50 ml. of methylene chloride was added. Dilution with 150ml. of petroleum ether (Skellysolve B) caused an oil to separate. Thesolvent was partially distilled at reduced pressure until about 25 ml.of solvent plus a semi-solid gum remained. The solvout was decanted andthe gum ground with Skellysolve B to give the product,6-(2,6-dimethoxybenzamido)-penicillanyl alcohol phenylcarbamate, as anamorphous solid which was collected by filtration and dried in vacuoover phosphorus pentoxide, 3.4 g. The infarared absorption spectrum hadtypical maxima for NH at 3300; fi-lactam at 1780; urethane at 1740;amide at 1670; and aromatic at 705 cmr A naIy.rz's.-Calcd. for C H N OS: C, 59.36; H, 5.61; N, 8.65. Found: C, 59.50; H, 6.02; N, 8.07.

6-triphenylmethylaminopenicillanyl alcohol.-A suspension of 4.97 g.(0.0100 mole) of potassium 6-(triphenylmethylamino)-penicillanate in 40ml. of water was acidified to pH 2.7 with 6 N sulfuric acid andextracted with two 200 ml. portions of ether. The combined etherextracts were washed once with 50 ml. of saturated sodium chloridesolution, dried briefly over sodium sulfate, and filtered. The filtratewas treated with 2.5 ml. of triethylamine and flashed to dryness at 33.The residue was flashed at 33 twice with 250 ml. portions of ethylacetate to remove moisture azeotropically. The gummy residue was thendried to a flufiy solid by pumping at 1 mm. over phosphorus pentoxidefor fifteen min utes. The fiuify solid was dissolved in 40 ml. of drytetrahydrofuran in a 250 ml. flask protected with a calcium chloridetube, and cooled to 10 in ice-salt. The solution was treated with 0.85ml. (0.009 mole) of ethyl chloroformate and stirred at l0 for 2.5minutes. A solution of 0.58 g. of sodium azide (0.0089 mole) in 3 ml. ofwater was added dropwise during 20 minutes, followed immediately by 15ml. of ice water. Solid sodium borohydride, 0.66 g. (0.0175 mole) wasadded during 28 minutes while the pH was held at 8.3-8.5 by the additionof glacial acetic acid.

The solution was diluted with 50 ml. of water, pH adjusted to 6.0 withacetic acid, and extracted with tWO 200 m1. portions of methylenechloride. The combined extracts were flashed to remove the solvent at 33and the residue, which contained acetic caid, was dissolved in ml. ofether. The ether solution was extracted with 50 ml. of 5% sodiumbicarbonate solution, dried, filtered, and flashed dry, leaving acrystalline residue of the product, 6-triphenylmethylarninopenicillanylalcohol, which was triturated with Skellysolve B, collected byfiltration and dried. The yield was 1.60 g. of white crystals, M.P.-170. It was recrystallized from ether and Skellysolve B to a constantM.P. 187 188. Infrared and NMR spectra were in complete accord with theexpected structure.

Analysis.-Calcd. for C2qH23N2O2S' /2H2O: C, H, 6.44; N, 6.18. Found: C,71.75, 71.80; H, 6.38, 5.87; N, 6.15.

6-triphenylmethylaminopenicillanyl acetate.-A solution of 55 mg. of6-triphenylmethylaminopenicillanyl alcohol in 1.0 ml. of aceticanhydride was heated on a steam bath for one hour. The solvent wasremoved under vacuum at 70 and the residual gum was flashed repeatedlywith benzene to remove traces of acetic acid and acetic anhydride. Itwas extracted into 15 ml. of hot Skellysolve B, cooled and decanted froma trace of insoluble material. Complete removal of solvent under vacuumleft 58 mg. (97%) of the product, 6-triphenylmethylaminopenicillanylacetate, as a fluffy, non-crystalline solid. Its infrared absorptionspectrum showed p-lactam at 1780; ester at 1745; aliphatic ester at1230; and aromatic bands at 1600, 1490, 770, 750 and 710 cor- Analysis.'Calcd. for C29H3ON203S: C, H, 6.21- Found: C, 71.50; H, 6.47.

13 14 6 aminopenicillanyl alcohol, p -toluenesulfonic acid of water, 6.4g. (0.17 mole) of sodium borohydride was salt.A solution of 0.75 g.(1.68 millimole) of 6-triadded in small portions during 25 minutes, thepH being phenylmethylaminopenicillanyl alcohol in 10 ml. of dry kept at88.5 by occasional additional of glacial acetic acetone was stirred with0.32 g. (1.68 millimole) of acid. The pH was then lowered to 6 withglacial acetic p-toluenesulfonic acid monohydrate for 30 minutes atacid, the mixture was diluted with 500 ml. of water and 25. The solventwas blown off with a stream of nitrothree extractions were made withmethylene chloride. gen and the gummy residue was triturated with 100ml. The combined extracts were dried for 30 minutes over of dry ether,which washed out the triphenylcarbinol anhydrous Na SO filtered andconcentrated in vacuo. (obtained from the ether solution in 81% purifiedyield An infrared curve indicated the presence of acidic mateandidentified by melting point and infrared spectrum) 10 rial in this gum;it was therefore dissolved in ether, and left the product,6-aminopenicillanyl alcohol, p-toluwashed twice with saturated NaHCOsolution, twice enesulfonie acid salt, as a filterable solid. The crudeyield with water and once with saturated NaCl solution. After ofnon-crystalline material was 0.63 g. It was repredrying over anhydrousNa SO the solution was concipitated five times from dry acetone by theaddition of centrated to yield the product as a tacky gum. After dryether, 0.28 g. (amorphous), M.P. ca. 100. Its indrying in vacuo for 15hours, the product, 6-(5-methy1- frared spectrum (in KBr) showed OH andNH absorp- 3pher1ylisoxazole-4-carboxamido) penicillanyl alcohol, tionat 2.92-2.96p, an intense B-lactam carbonyl at 5.61 was obtained as ayellowish solid; yield 19.2 g. A sample and sharp, intense bands at 8.3,8.9, 9.65, 9.9, 12.25 and of the solid crystallized from ether; M.P.122-123.5.

14,6, characteristic of the toluenesulfonic acid. Afterrecrystallization from benzene-Skellysolve B, it had Analysis.Calcd. forC H N O S C, 48.11; H, MP. 123 124. 5.92. Found: C, 48.40; H, 5.83.AnalySiS.Calcd. for C H N O S: C, 58.9; H, 5.46;

S CH3 N, 10.9. Found: C, 58.8; H, 5.38; N, 10.8. An infrared absorptionspectrum (KBr) showed char- N2N CH OH C CH3 acteristic absorption maximaat 1785 (,B-lactam) and 25 1575 (amide) cmf 6 aminopenicillanylalcohol.6 aminopenicillanyl Sodium 6 (5 methyl 3 phenylisoxazole 4caralcohol p-toluenesulfonic acid salt, 1.028 g. (2.72milliboxamido)-penicillanyl alcohol acid succinate.A solumoles), wasadded to a mixture of 5.12 ml. of water, 228 tion of 4.0 g. (0.010 mole)of 6-(5-methyl-3-phenylisoxamg. of sodium bicarbonate, and 51 ml. ofethyl acetate. Zole-4-carboxamido)-penicillanyl alcohol, 1.0 g. (0.010The resulting mixture was shaken vigorously and the mole) of succinicanhydride, and fifteen drops of triethyl acetate solution was separated.The aqueous layer ethylamine in 50 ml. of methylene chloride wasrefluxed was extracted twice more with 50 m1. portions of ethyl for 30minutes and then evaporated in vacuo. The residue acetate. The combinedethyl acetate extracts were dried was dissolved in 75 ml. of methylisobutyl ketone and over sodium sulfate, filtered, and flashed todryness at extracted twice with 30 ml. portions of 5% sodium bicar- 30.The residue was dissolved in 50 ml. of ethyl acetate bonate solution.The combined extracts were washed with adn precipitated by the additionof 600 ml. of n-pentane. ether (30 ml.), acidified to pH 2 with 20%sulfuric acid The resulting solid, 6-aminopenicillanyl alcohol, weighedand extracted twice with 35 ml. portions of ether. The 278 mg. and hadM.P. 86.588.0. Its infrared spectrum combined ethereal extracts werewashed twice with 10 (in KBr) showed absorption maxima at 2.95-3.01 (OHml. portions of water, dried over sodium sulfate, filtered, and NH),3.37 1. (OH, with shoulders at 3.40 and 3.4811) and treated with 3.5 ml.(0.01 mole) of a solution and 5.63 (B-lactam). The characteristictoluenesulfonic of sodium 2-ethylhexanoate in n-butanol. The product,acid absorptions above 8;]. were absent. 50 sodium 6 (5 methyl 3phenylisoxazole 4 carboxamido)-penicillanyl alcohol acid succinate,crystal- Example 6 lized on standing at 8 for 17 hours. It was collectedand a dried in vacuo over phosphorus pentoxide; weight, 1.5 g.; HFCNHClHOH OCH3 lVLP. 196 1981 (dec). 'fThelgfrared aslgsorptlion specrumcontame max1ma or at 33 B-actam at L O C N CH CH2OH 1780; ester at 1730;amide at 1670; carboxylate at 1590;

0 primary ester at 1160; aromatic at 1570 and 705 CH1.1.

6 methyl 3 phenylisoxazole 4 carboxamido)- Analysis.Calcd. for C H N OSNa- /2H O: C,

penicillanyl alcohol.A solution of 9.1 g. (0.085 mole) 53.27; H, 4.86;N, 8.10. Found: C, 53.50; H, 4.72; N. of ethyl chloroformate in 40 ml.of tetrahydrofuran was 8.16.

fl) /S CH3 h t N O=C-NCHCHzOC-NH added during 20 minutes to a stirredsuspension of 44.3 6 (5 :methyl 3 phenylisoxazole-4-carboxamido)- g.(0.085 mole) triethylammonium 6-(5-methyl-3-phenpenicillanyl alcoholphenylcarbamate.A solution of ylisoxazole-4-carboxamido)-penicillanatein 300 ml. of 870 mg. (2.2 millimoles) of6-(5-methyl-3-phenylisoxaztetrahydrofuran, the temperature beingmaintained at ole-4-carboxamido)-penicillanyl alcohol and 330 mg. (3.010. The mixture was stirred for 2 hours at 10 and millimoles) of phenylisocyanate in 20 ml. of dimethyla solution of 5.5 g. (0.085 mole) ofsodium azide in 50 for-mamide was allowed to stand at 25 for ten days.It ml. of water was added during 25 minutes while keeping was dilutedwith :ml. of water and cooled. The crystalthe temperature at 0-5. Afterthe addition of ml. 75 line solid was collected, dissolved in 75 ml. ofethyl acetate and concentrated to dryness in vacuo. The residue wasredissolved in ethyl acetate, concentrated to a low volume and filteredto remove a small amount of crystalline product which was identified ascarbanilide by MP. and infrared spectrum. Dilution of the ethyl acetatesolution with petroleum ether (Skellysolve B B.P. 6068) gave theproduct, 6-(5-methyl-3-phenylisoxazole-4-carboxamido)-penicillanylalcohol phenylcarbamate, as a crystalline solid. This was dissolved inmethylene chloride, filtered to remove a trace of insoluble material,concentrated to dryness in vacuo, and recrystallized in turn from ethylacetate and benzene-Skellysolve B. After drying in vacuo over phosphoruspentoxide, the product weighed 300 mg. (33%) and had M.P. 151151.5. Theinfrared spectrum showed absorptions for NH at 3280; ,B-lactam at 1785;carbamate at 1738; amide at 1670; and aromatic at 765 and 700 cmfAnalysis.Calcd. for C H N O S: C, 61.50; H, 5.16; N, 11.10. Found: C,61.40, 61.80; H, 5.07, 4.89; N, 11.05.

Example 7 o s CH3 @ormdasrporno \C/CH3 NIH 31 IHOHzOH :0 5 5 6(D-a-carbobenzoxyaminophenylacetamido)-penicillanyl alcohol.A solutionof 34 g. (0.070 mole) of 6 (Du-carbobenzoxyaminophenylacetamido)-penicillanic acid and ml. (0.071mole) of triethylamine in 300 ml. of tetrahydrofuran was cooled to -10in an apparatus protected from atmospheric moisture by means of acalcium chloride drying tube and 7 ml. (0.070 mole) of ethylchloroformate was added dropwise over a period of ten minutes. Themixture was stirred for one hour at 10 and then a solution of 4.6 g.(0.070 mole) of sodium azide in 50 :ml. of water was added dropwise overa period of 30 minutes at 10 to --8. After five min- -utes a solution of19.2 g. (0.141 mole) of sodium acetate trihydrate in 100 m1. of waterwas added and the tem perature was allowed to come to 0. Over a periodof one-half hour, 5.3 g. (0.141 mole) of sodium borohydride was added insmall portions to the rapidly stirred mixture while the temperature wasmaintained at 0 to 5. Vigorous gas evolution occurred after eachaddition. The mixture was maintained in the range of pH 7.5 to 8.1 bythe addition of glacial acetic acid as needed. After the addition ofsodium borohydride was complete, the reaction mixture was stirred forone-half hour at 0 to 5 and adjusted to pH 6.0 with 6 N hydrochloricacid. Wa ter (500 ml.) was added and the mixture extracted with one 500ml. portion of methylene chloride. The methylene chloride extract waswashed with two 500 ml. portions of water, dried with sodium sulfate,filtered and the solvent removed at reduced pressure to give theproduct, 6 (D m-carbobenzoxyaminophenylacetamido)-penicillanyl alcohol,as a viscous oil; yield 33 g.

6-(D-a-aminophenylacetamido)-penicillanyl alcohol- A solution of 9.00 g.(0.0192 mole) of 6-(D-a-carbobenzoxyaminophenylacetamido)-penicillanylalcohol, 200 ml. of isopropyl alcohol, 25 ml. of water and 3 ml. ofglacial acetic acid was hydrogenated on a Paar hydrogenation apparatusat an initial pressure of 50 p.s.i1. for three hours in the presence of10 g. of 30% palladium on diatomaceous earth. The catalyst was removedby filtration and most of the solvent was distilled from the filtrate atreduced pressure. Water (75 ml.) was added to the residue and themixture was extracted with 150 ml. of methylene chloride. The aqueousphase which was found to be at pH 4.5 was adjuster to pH 7.5 with 20%sodium hydroxide and extracted with 50 ml. of methylene chloride. Themethylene chloride extract was dried with sodium sulfate, filtered, andthe solventremoved at reduced pressure to give 1.4 g. (16%) of product,-(D-a-aminophenylacetamido)-penicillanyl alcohol, as a viscous oil whichsoon solidified. The infrared absorption spectrum of this material inmethylene chloride showed maxima for water at 3600; OH and NH at 3300;fl-lactam at 1780; and amid at 1680 and 1520 cmr' Analysis.Calcd. for CH N O S. /2H O: C, H, 6.44; N, 12.20. Found: C, 55.65, 55.50; H, 6.37,6.42; N, 12.68.

6-phthalimidopenicillanic acid azide.A solution of 34.6 g. (0.10 mole)of -6-phthalimidopenicillanic acid and 14 ml. (0.1 mole) oftriethylamine in 300 ml. of tetrahydrofuran was cooled to 10 and asolution of 10.8 g. (0.1 mole) of ethyl chloroformate in 50 m1. oftetrahydrofuran was added. The resulting mixture was stirred at 10 forone hour, and then a solution of 6.5 g. (0.10 mole) of sodium azide in50 ml. of water was added during a period of 30 minutes. The reactionmixture was diluted with an equal volume of water and the crystallineazide thus formed was collected by filtration, yield 30 g. It wascharacterized by its infrared absorption spectrum which exhibited maximafor azide at 2164; phthalimide at 1825, 1725 and 1710; ,B-lactam at1780; aromatic ring at 792 and 717 cmf 6 phthalimido2,2-dimethyl-3-penamylisocyanate.- When 6-phthalimidopenicillanic acidazide was dried under vacuum for two days at room temperature, it wasquantitatively converted to the corresponding crystalline isocyanate,m.p. 75 (dec.). It infrared absorption spectrum showed an intenseisocyanate band at 2275; phthalimide at 1806 and 1733; B-lactarn at1797; and aromatic ring at 795 and 716 cm.

Analysis.Calcd. for C16H13N304SI C, H- N, 12.24. Found: C, 55.99, 55.64;H, 3.60, 3.63; N, 12.00, 12.29.

Benzyl 2,2-dimethyl-6-phthalimido-3-penamyl carbamate.-A solutioncontaining 18.5 g. (0.050 mole) of 6- phthalimidopenicillanic acid azideand 10.8 g. (0.10 mole) of benyl alcohol in ml. of benzene was warmed toabout 75 and stirred until evolution of nitrogen ceased. The reactionmixture was evaporated to dryness at reduced pressure and thecrystalline residue of the product, benzyl2,2-dimethyl-6-phthalimido-3-penarnyl carbamate, was recrystallized fromacetone-water and then from isopropyl alcohol to a constant MP. of 161-162. The yield was 20.5 g. Its infrared absorption spectrum had bandsascribed to NH at 3400; B-lactam, phthalimide and urethane carbonyls intwo rather broad absorptions centering at 1785 and 1720; and aromaticbands at 796 and 716 cmf Analysis.-Calcd. for C H N O S: C, 61.19; H,4.65; N, 9.31. Found: C, 61.27; H, 4.86; N, 9.57.

6-phthalimidopenicillanyl alcohol.A solution containing 17.3 g. (0.050mole) of 6-phthalimidopenicillanic acid and 7 ml. (0.05 mole) oftriethylamine in 150 ml. of dry tetrahydrofuran was cooled to 10". Tothe cooled and vigorously stirred solution was added a solution of 5.4g. (0.050 mole )of ethyl chloroformate in 25 ml. of tetrahydrofuran. Theresulting mixture was stirred for 1 hour at 10". A solution of 3.25 g.(0.050 mole) of sodium azide in 25 ml. of water was then added dropwiseduring 30 minutes, the temperature being kept between and Stirring wascontinued for a further minutes, and the mixture was then diluted with100 ml. of cold water. The acid azide which precipitated was collectedby filtration, washed with cold water and dried briefly by suction onthe water pump. It was then dissolved in a mixture of 300 ml. of dioxaneand 50 ml. of water, and the solution was cooled to 5 To the stirredsolution was added 3.7 g. (0.10 mole) of sodium borohydride in portionsso that the temperature was maintained at 5. The pH of the solution waskept at 8.0-8.5 by suitable addition of glacial acetic acid. After theaddition was completed, the mixture was stirred for 25 minutes at 5,then diluted with 250 ml. of water and the pH adjusted to 6.5 byaddition of more acetic acid. The acidic solution was extracted threetimes with 200 ml. portions of methylene chloride, and the combinedextracts were washed successively with 5% aqueous sodium bicarbonatesolution and with cold water. After the extracts were dried (anhydrousmagnesium sulfate) the solvent was evaporated to leave a clear gum,which was dissolved in a mixture of ethyl acetate and anhydrous etherand the solvents removed at 30/15 mm. The residue of the product,6-phthalimidopenicillanyl alcohol, was then a glass-like solid which, ontrituration with cold isopropyl alcohol, became crystalline. Yield 8.6g. A small portion was recrystallized for analysis from isopropylalcohol and gave white needles, M.P. 160162. Its infrared absorptionspectrum showed maxima for OH at 2.85; phthalimide at 1785 and 1720;B-lactam at 1760; primary alcohol at 1350, 1310 and 1045; aromatic at793 and 720 cmf Its NMR spectrum showed all of the expected resonancelines, as well as the presence of isopropyl alcohol.

Analysis-Calcd. for C H H O S- AC H O: C, 58.01; H, 5.56; N, 7.73.Found: C, 57.85; H, 6.02; N, 7.72.

Potassium salt of 6-(2'-carboxybenzamido) penicillanyl alcohol.Asolution of 10 g. (0.030 mole) of 6-phthalimidopenicillanyl alcohol in200 ml. of tetrahydrofuran and 200 ml. of water was maintained at pH10-11 by the constant addition of 1 N sodium hydroxide. When 29 ml. ofbase (0.029 mole) had been added, the solution was extracted with three200 ml. portions of methylene chloride, the aqueous phase was acidifiedto pH 3 with 40% phosphoric acid and again extracted with two 200 ml.portions of methylene chloride. The combined extracts of the acidifiedsolution were dried over sodium sulfate, filtered, and evaporated underreduced pressure. The residue of 6-(2'-carboxybenzamido)penicillanylalcohol was dissolved in 100 ml. of ethyl acetate and treatedsuccessively with three 0.0050 mole portions of potassiumZ-ethylhexanoate, the crystalline precipitate which formed with eachtreatment being collected by filtration and dried. Infrared and 'NMRspectra showed the third fraction to be the pure potassium salt of 6-(2-carboxybenzamido)penicillanyl alcohol, 1.8 g., with maxima for 0H and NHat 3600 to 3000; B-lactam at 1770; amide at 1660; carboxylate at 1400;primary alcohol at 1310 and 1045;. and 1,2-disubstituted benzene at 750cmr Example 9 N-carbobenzoxy-6-aminopenicillanyl alcohol.A sus pensionof 22.2 g. (0.05 mole) of N-carbobenZoxy-6- aminopenicillanic acid inthe form of its triethylamine salt in 150 ml. of tetrahydrofuran wascooled to 10 in an ice-salt bath. To this cooled solution was added withstirring a solution of 5.4 g. (0.05 mole) of ethyl chloroformate in 25ml. of tetrahydrofuran. The resulting mixture was stirred and cooled at10 for 2 hours. At this point, a slurry remained although of visiblyaltered character. Then a solution of 3.25 g. of (0.05 mole) of sodiumazide in 25 ml. water was added dropwise over a 30 minute period. Thereaction mixture was then diluted with 50 ml. water containing 6.8 g.(0.05 mole) of sodium acetate trihydrate to bring the pH of the mediumto 7.5. Then small portions of sodium borohydride totalling 3.7 g. (0.10mole) were added over a 30-minute period during which time thetemperature was maintained between 0 and 5 and the pH between 7.5 and8.3 by occasional addition of glacial acetic acid. At the end ofaddition, the pH of the medium was brought to 6.0 with glacial aceticacid and then 250 ml. of water added. The mixture was extracted threetimes with 100 ml. portions of methylene chloride and the combinedextracts containing the product, N-carbobenzoxy-6aminopenicillanylalcohol, were dried over magnesium sulfate overnight. After removal ofsolvent, a portion of the residue (14.0 g.) was examined by infrared andNMR spectroscopy. Both spectra were consistent with the product being N-carbobenzoxy-6-aminopenicillanyl alcohol contaminated bytetrahydrofuran. The residue was dried thoroughly under vacuum forming afoamy glass which resisted all attempts at crystallization.

Analysis.Calcd for C H N O.,S: C, 57.11; H, 6.0; N, 8.3. Found: C, 57.1;H, 5.8; N, 8.7, 8.6.

Example 10 6-phenylacetamidopenicillanyl alcohol.A flame-dried 500 ml.three-neck round-bottom flask equipped with a stirrer, thermometer andpressure-compensated dropping funnel was charged with a suspension of10.9 g. (0.025 mole) of benzylpenicillin triethylammonium salt in ml. ofdry tetrahydrofuran and placed under a nitrogen atmosphere. To thevigorously stirred suspension at -l0 a solution of 2.7g. (0.025 mole) ofredistilled ethyl chloroformate in 15 ml. of dry tetrahydrofuran wasadded during ten minutes. After stirring the resulting mixture for twohours at -.-'8, 1.9 g. (0.050 mole) of sodium borohydride was added insmall portions over a fiveminute period. The reaction mixture was thenstirred for twenty-five minutes without the cooling bath. The mixturewas diluted with 125 ml. of water and the product was extracted with twoml. portions of methylene chloride. The combined methylene chlorideextracts were dried over anhydrous sodium sulfate, filtered and evapo-19 rated to dryness at reduced pressure to leave6-phenylacetamidopenicillanyl alcohol as the residue. The product, 7.5g. of brittle foam, was shown by its infrared and NMR spectra to beidentical with the d-phenylacetamido-penicillanyl alcohol obtained inExample 1.

In the present invention a penicillin alcohol is defined as a compoundof the formula in which R represents the side chain of any of the knownpenicillins other than those containing a group which is altered byreaction with sodium borohydride such as a ketonic carbonyl.

In the present invention a penicillin acid azide and a penicillinisocyanate are defined as a compound of the formula in which Rrepresents the side chain of a known penicillin and Y is and -NCOrespectively.

While in the foregoing specification various embodiments of thisinvention have been set forth in specific detail and elaborated for thepurpose of illustration, it will be apparent to those skilled in the artthat this invention is susceptible to other embodiments and that many ofthe details can be varied widely without departing from the basicconcept and the spirit and scope of this invention.

We claim:

1. A member selected from the group consisting of a compound of theformula wherein R represents a member selected from the group consistingof hydrogen, amino, carbobenzoxyamino, phenyl, fiuoro, chloro, bromo,iodo, hydroxy, (lower)alkanoyloxy and (lower)alkoxy;

X represents a member selected from the group consisting of oxygen andsulfur;

R and R each represent a member selected from the ilrloulp consisting ofhydrogen, phenyl, and (lower) R' represents (lower)alkyl;

R and R each represent a member selected from the group consisting of(lower)alkyl or Ar and at least one of R and R represents (lower) alkyl;

R represents a member selected from the group consisting of(lower)alkyla.mino, di(lower)alkylamino, cycloalkylamino having from 3to 7 carbon atoms inclusive, 'allylamino, diallylamino, phenyl(lower)alkylamino, morpholino, lower(alkyl)morpholino,di(lower)alkylmorpholino, morpholino (lower) alkylamino, pyrrolidino,(lower) alkylpyrrolidino, di (lower) alkylpyrrolidino, N,Nhexamethyleneimino, piperidino, lower(alkyl)piperidino,di(lower)alkylpiperidino, 1,2,5,6-tetrahydropyridino, N (lower)alkylpiperazino, N-phenylpiperazino, N-(lower)alkyl (lower)alkylpiperazino, N (lower) alkyl-di-(lower) alkylpiperazino,furfuryl-amino, tetrahydrofurfurylamino, N-(lower)alkyl-N-furfurylamino, N-alkyl-N- anilino and (lower) alkoxyanilino; Z Zand Z each represent a member selected from the group consisting of(lower) alkyl and the monovalent radical of the formula wherein R R andR are each a member selected from the group consisting of hydrogen,chloro, bromo, iodo, trifluoromethyl, phenyl, (lower)alkyl and(lower)alkoxy, but only one R group may represent phenyl; and Y is amonovalent radical selected from the group consisting of (ll-Na and NCO.

2. A member selected from the group consisting of compounds having theformulae /S\ /CHa HaN-CH-CH C-CH3 O=CN CH( J-Na wherein R represents amember selected from the group consisting of hydrogen, amino,carbobenzoxyarnino, phenyl, fiuro, chloro, bromo, iodo, hydroxy, (lower)alkanoyloxy and (lower)alkoxy; X represents a member selected from thegroup consisting of oxygen and sulfur; R and R each represent a memberselected from the group consisting of hydrogen, phenyl and (lower)alkyl;R represents (lower)alkyl; R and R each represents (lower)alkyl or Arand at least one of R and R represents (lower)alkyl; R represents amember selected from the group consisting of (lower)alkylamino, di-(lower)alkylarnino, cycloalkylamino having from 3 to 7 carbon atomsinclusive, allylamino, diallylamino, phenyl(lower)alkylamino,morpholino, lower(alkyl) morpholino, di(lower)alkylmorpholino,morpholino- (lower)alkylamino, pyrrolidino, (lower)alkylpyrrolidino,di(lower)alkylpyrrolidino, N,N-hexamethyleneirnino, piperidino,lower(alkyl)piperidino, di(lower)alkylpiperidino,1,2,5,6-tetrahydropyridino, N-(lower)alkylpiperazino,N-phenylpiperazino, N-(lower) alkyl(lower)alkylpiperazino,N-(lower)alkyl-di-(lower)alkylpiperazino, furfurylamino,tetrahydrofurfurylamino, N-(lower)alkyl- N-furfurylamino,N-alkyl-N-anilino and (lower)alkoxyanilino; Z Z and Z each represent amember selected from the group consisting of (lower)alkyl and themonovalent radical of the formula wherein R R and R are each hydrogen,chloro, bromo, iodo, trifluoromethyl, nitro, (lower)alkyl orlower)alkoxy;

R represents a member selected from the group consisting of(lower)alkyl, (lower)cycloalkyl, naph- 23 24 thyl, benzyl and phenethyl;and Arrepresents the 7. A compound of claim 1 having the formulamonovalent radical of the formula wherein R is (lower)alkyl.

8. A compound of claim 1 having the formula 0113 (I3CH3 3 a N H H O 0one C' C S /H J N w p 5 H O o e m H C C 0 o 5 3 a m was no I Sd ey r a Pm 6f f0 m 2 g r R m cm d e n m m m 2 W .m k V In. a an h m O 6W: 1 we m1h m (t 1 c mm f nm 0 W i d e n Id U pfi 0 m P m5 RSIW .mm 8 h m Wma 12.A compound of claim 1 having the formula I CH-(E-NH-CH-CH C-CHa H J H nm LLLWM l OCH;

l G CH3 No references cited.

I I NICHOLAS s. RIZZO, Primary Examiner. ON-C US. Cl. X.R.

wherein R represents (l0wer)alkyl.

32 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 354,556 Dated Julv 8 196 Inventor(s) Lee C. Cheney and Yvon G. Perron Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In the Claims: Claim 1, column PO, that portion of the formula betweenlines 5 and 8, reading:

N N -CH HEN I sho 10 (1 0:0 u A Pea O==C that portion of the formulabetween lines 2 4 and 28, reading:

C --OH should read C NH- In claim 13 column 2N, lines +7 through 52,that portion of the formula which reads:

I C should read O C -C SIGNED AND SEALED MAR 2 41970EdwardlLFIetcher,Jr. Attesting Officer Commissioner of Patents WILLIAME. SGHUYLER, JR.

